LTA4-h is a monomeric, soluble 69 kD zinc metalloenzyme. It catalyses two reactions: the stereospecific epoxide hydrolase reaction to convert LTA4 to leukotriene B4 (LTB4) and a peptidase cleavage of chromogenic substrates. Leukotriene B4 (LTB4) is a major pro-inflammatory mediator. LTA4-h and receptors to LTB4 are known to be elevated in a number of human lung diseases including cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). Additionally, elevated levels of LTA4-H have been located at active demyelinating lesions in the brains of patients with multiple sclerosis (MS).
LTA4-h inhibitors have been described, for example, in U.S. Pat. No. 7,737,145 and U.S. Patent Application Publication No. 20100210630A1, the contents of each of which are incorporated by reference herein. A specific LTA4-h inhibitor described in these patent publications is 4-{[(1S,4S)-5-({4-[4-oxazol-2-yl-phenoxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}benzoic acid. In preclinical studies, this compound was shown to reduce the progression of chronic inflammation in several animal models. 4-{[(1S,4S)-5-({4-[4-oxazol-2-yl-phenoxy]phenyl}methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}benzoic acid is in development for the treatment of specific inflammatory disorders.
It would be advantageous to develop additional methods of inhibiting LTA4-h in human patients.